Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].C([Li])CCC.[O:14]1[CH:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15]1.B(F)(F)F.CCOCC.Cl>C1COCC1>[F:1][C:2]1[C:3]([F:8])=[CH:4][CH:5]=[CH:6][C:7]=1[CH2:15][CH:16]([OH:14])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCC1CO1
Reactant: Fc1ccccc1F
Agent: Cl
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCC(O)Cc1cccc(F)c1F
Temperature: -70 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
To a stirred solution of 1,2-difluorobenzene 1 (20.0 g, 0.175 mol) in dry THF (300 ml) was added dropwise a solution of 2.5 M n-butyllithium (68 ml, 0.17 mol) at −70° C. under dry nitrogen. The addition rate was such that the temperature did not rise above −60° C. After the addition was completed the reaction was stirred at −70° C. for 2 h. 1,2-Epoxyoctane (21.6 g, 0.169 mol) was added slowly followed by the dropwise addition of boron trifluoride etherate (21 ml, 0.17 mol). The mixture was allowed to warm to room temperature overnight, acidified with 10% hydrochloric acid and extracted into ether. The combined extracts were washed with sat. aqueous sodium chloride and evaporated to give a viscous liquid. Kugelrohr distillation (130° C., 0.15 mm Hg) yielded 1-(2,3-difluorophenyl)-octan-2-ol (30.8 g, 74%) which crystallised on standing; Vmax 3370 br (OH), 2950, 2920, 2850, 1620, 1590, 1480 s, 1280, 1205, 1070 br, 825, 775, and 730 cm−1, δH 0.88 (3 H, t, Me), 1.23-1.40 (10H, m, CH2), 1.40-1.58 (4 H, m overlapping br s, CH2CHOH and OH), 2.72 (1 H, ddd, J16, 8 and 2 Hz, ArCH2), 2.91 (1 H, ddd, J16, 6, and 2 Hz, ArCH2), 3.86 (1 H, m, CHOH), and 6.94-7.09 (3 H, m, ArH); m/z 242 (M+), 225, 198, 157, 139, 128, and 97.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[CH:6]1[CH:7]=[C:8]2[CH2:22][C:16]3[CH:17]=[CH:18][CH:19]=[C:20]([OH:21])[C:15]=3[C:13](=[O:14])[C:9]2=[C:10]([OH:12])[CH:11]=1>C1C=CC=CC=1.N1C=CC=CC=1>[OH:21][C:20]1[C:15]2[C:13](=[O:14])[C:9]3[C:8](=[CH:7][CH:6]=[CH:11][C:10]=3[OH:12])[CH:22]([C:1](=[O:4])[CH2:2][CH3:3])[C:16]=2[CH:17]=[CH:18][CH:19]=1
Reactant: CCC(=O)Cl
Reactant: O=C1c2c(O)cccc2Cc2cccc(O)c21
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCC(=O)C1c2cccc(O)c2C(=O)c2c(O)cccc21

Procedure:
24.9 g (0,269 moles) propionyl chloride is added, while stirring, to a mixture containing 50.9 g (0,225 moles) anthralin in 1575 ml of benzene and 27.5 ml of pyridine. The reaction mixture is cooked using a return condenser for 20 hours while stirring. The solution is filtered and the filtrate is evaporated dry under a lowered pressure. The residue is crystallized out from acetic acid. Yield 27.6 g (43.5% of the theoretical). M.p.=149°-154° C.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]3OCC[O:16]3)[CH:10]=2)=[O:7])=[CH:4][CH:3]=1.Cl>O1CCOCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[O:16])[CH:10]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Nc1cccc(C2OCCO2)c1)c1ccc(Cl)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=Cc1cccc(NC(=O)c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.4 %

Procedure:
A solution of 4-chloro-N-(3-[1,3]dioxolan-2-yl-phenyl)-benzamide (14.33 g, 47.2 mmol) in 1,4-dioxane (120 mL) is treated with 1N aq. HCl (120 mL) at RT for 1 h then at 60° C. for 30 min. The reaction mixture is cooled down to RT and diluted with ethyl acetate (100 mL). The organic phase is separated and the aqueous phase is extracted twice with ethyl acetate (100 mL). The combined organic phases are washed with brine (200 mL) and dried over MgSO4. After evaporation of the organic solvents the residue is triturated with diethyl ether to give the title compound (10.34 g, 84%) as a beige powder; LC-MS B: tR=0.83 min; [M+H]+=259.82.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[C:8]1[C:20]2[N:19]3[CH:21]=[CH:22][N:23]=[C:18]3[C:17](=[O:24])[NH:16][C:15]=2[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2.CN(C)C=O>[Pd].C(O)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH:8]1[C:20]2[N:19]3[CH:21]=[CH:22][N:23]=[C:18]3[C:17](=[O:24])[NH:16][C:15]=2[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2
Reactant: O=c1[nH]c2c3ccccc3c(=Cc3ccccn3)c2n2ccnc12
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=c1[nH]c2c(n3ccnc13)C(Cc1ccccn1)c1ccccc1-2
Yield: 49.7 %

Procedure:
The procedure is performed as in Example 21, but starting with 0.7 g of 10-(2-pyridylmethylene)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one, 200 ml of dimethylformamide, 5 ml of acetic acid and 70 mg of 10% palladium on charcoal. The crude product (1.1 g) is purified by trituration in a mixture of 10 ml of dichloromethane and 40 ml of ethyl ether, followed by crystallization in 25 ml of dimethylformamide and 40 ml of water. 0.35 g of 10-(2-pyridylmethyl)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one is obtained, in the form of a light beige solid melting above 260° C. (Analysis % calculated C: 72.60, H: 4.49, N: 17.82, O: 5.09, % found C: 72.5, H: 4.6, N: 17.9, O: 5.5).
Reaction SMILES: [Cl:1][C:2]([Cl:20])([Cl:19])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[CH2:7][CH2:6]1)=[O:4].[Cl:21][S:22](O)(=[O:24])=[O:23]>ClCCl>[Cl:20][C:2]([Cl:1])([Cl:19])[C:3]([N:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:16]=[C:15]([S:22]([Cl:21])(=[O:24])=[O:23])[CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[CH2:9][CH2:10]1)=[O:4]
Reactant: COc1ccccc1N1CCN(C(=O)C(Cl)(Cl)Cl)CC1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)Cl)cc1N1CCN(C(=O)C(Cl)(Cl)Cl)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
A solution of 2-(4-trichloroacetylpiperazin-1-yl) anisole (D1) (10 g) in dichloromethane (115 ml) was added over 0.3 h to ice-cooled chlorosulfonic acid (52 ml). After 0.5 h at 0° C. then 1 hour at ambient temperature, the solution was poured onto a mixture of ice-water (500 g) and dichloromethane (500 ml) with rapid stirring. The layers were separated and the organic phase was washed with water (2×800 ml), dried (MgSO4) and concentrated to give the title compound (D2) as a foam (6.0 g, 46%), MH+ 435/437.
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]1[CH2:15]O.[CH:17]1([N:20]2[C:28]3[CH:27]=[CH:26][N:25]=[CH:24][C:23]=3[NH:22][C:21]2=[O:29])[CH2:19][CH2:18]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C([O-])=O)=NC([O-])=O>C1COCC1>[CH:17]1([N:20]2[C:28]3[CH:27]=[CH:26][N:25]=[CH:24][C:23]=3[N:22]([CH2:15][C:7]3[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][F:1])[C:14]4[C:9]([N:8]=3)=[N:10][CH:11]=[CH:12][CH:13]=4)[C:21]2=[O:29])[CH2:19][CH2:18]1
Reactant: O=c1[nH]c2cnccc2n1C1CC1
Reactant: OCc1nc2ncccc2n1CCCCF
Agent: O=C([O-])N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1n(Cc2nc3ncccc3n2CCCCF)c2cnccc2n1C1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.3 %

Procedure:
To a suspension of (1-(4-fluorobutyl)-1H-imidazo[4,5-b]pyridin-2-yl)methanol 42-5 (958 mg, 4.3 mmol), 1-cyclopropyl-1H-imidazo[4,5-c]pyridin-2(3H)-one 10-d (950 mg, 5.15 mmol) and triphenylphosphine (1350 mg, 5.15 mmol) in 30 ml dry THF was added (E)-diïsopropyl diazene-1,2-dicarboxylate (1.26 ml, 6.43 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The precipitate was filtered off and washed with some diethyl ether to obtain the title product as a white powder (1036 mg, 63%).
Reaction SMILES: [O:1]=[C:2]([CH3:6])[CH2:3][C:4]#[N:5].CC(N(C)C)=O.[CH3:13][N:14]([CH:16]=O)[CH3:15]>>[CH3:15][N:14](/[CH:16]=[C:3](/[C:2](=[O:1])[CH3:6])\[C:4]#[N:5])[CH3:13]
Reactant: CN(C)C=O
Reactant: CC(=O)CC#N
Solvent: CC(=O)N(C)C
Product: CC(=O)/C(C#N)=C/N(C)C

Procedure:
3-Oxo-butyronitrile (113 g, 1.36 mol) and DMF.DMA (215 g, 1.81 mol) were heated to 80° C. for two hours. The solvents were then removed under vacuum to yield a solid. The solid was partitioned between ethyl acetate (1.5 L) and saturated sodium bicarbonate solution (1 L). The layers were separated and the aqueous layer was extracted with ethyl acetate (1.5 L). The organic layers were combined and the solvent removed under vacuum to yield the title compound as a solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:21]=C)=[C:4]([CH:9]=[C:10]([CH2:13][C:14]2[CH:15]=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=2)[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].CC(C)=[O:25].C(#N)C.I([O-])(=O)(=O)=O.[Na+]>[Os]=O.O>[CH:21]([C:3]1[C:2]([CH3:1])=[C:11]([CH3:12])[C:10]([CH2:13][C:14]2[CH:15]=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=2)=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])=[O:25]
Reactant: CC(C)=O
Reactant: C=Cc1c(C(=O)OC)cc(Cc2ccc(C)nc2)c(C)c1C
Agent: O=[Os]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cc(Cc2ccc(C)nc2)c(C)c(C)c1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3,4-dimethyl-5-((6-methylpyridin-3-yl)methyl)-2-vinylbenzoate (0.44 g) in a mixed solvent of acetone (5.40 mL)-acetonitrile (5.40 mL)-water (5.40 mL) were added osmium oxide (fixed catalyst I) (0.19 g) and sodium periodate (1.59 g), and the mixture was stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.44 g) as a crude product. This compound was used in the next step without an additional purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:15][C:8]2[N:9]=[C:10]([NH2:14])[N:11]=[C:12](Cl)[C:7]=2[CH:6]=1)=[O:4].[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:15][C:8]2[N:9]=[C:10]([NH2:14])[N:11]=[C:12]([NH:23][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2c(Cl)nc(N)nc2s1
Reactant: NCc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1cc2c(NCc3ccccc3)nc(N)nc2s1
Temperature: 25 °C

Procedure:
The 2-amino-4-chloro-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (100 mg, 0.39 mmol), benzylamine (100 μL) in 4 mL of THF are submitted to MW irradiation at 110° C. for 35 mins. The reaction was cooled to room temperature and worked up (acidic) and purified using standard conditions for a neutral compound.
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([OH:13])=O)[C:7](=[O:18])[CH:6]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:60][C:61]1([CH3:73])[O:65][C@H:64]([CH2:66][N:67]2[CH:71]=[CH:70][C:69]([NH2:72])=[N:68]2)[CH2:63][O:62]1>CN(C)C=O.C(OCC)(=O)C>[CH3:60][C:61]1([CH3:73])[O:65][C@H:64]([CH2:66][N:67]2[CH:71]=[CH:70][C:69]([NH:72][C:11](=[O:13])[C@@H:10]([N:8]3[CH2:9][C:5]([O:4][C:3]4[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:2]=4[F:1])=[CH:6][C:7]3=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16])=[N:68]2)[CH2:63][O:62]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: CC(C)C[C@@H](C(=O)O)N1CC(Oc2ccc(F)cc2F)=CC1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2ccc(F)cc2F)=CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
A solution of (S)-2-[4-(2,4-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (0.49 g, 1.53 mmol) in N,N-dimethylformamide (5.9 mL) at 25° C. was treated with N,N-diisopropylethylamine (0.76 mL, 4.59 mmol), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (1.01 g, 2.29 mmol) and a solution of 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 0.31 g, 1.60 mmol) in N,N-dimethylformamide (0.5 mL). The reaction was stirred at 25° C. overnight. At this time, the reaction was diluted with ethyl acetate (100 mL) and was washed with a saturated aqueous sodium bicarbonate solution (1×150 mL) and a saturated aqueous sodium chloride solution (1×150 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 50-75% ethyl acetate/hexanes) afforded (S)-2-[4-(2,4-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.63 g, 81%) as a light orange foam: HR-ES-MS m/z calculated for C25H30N4O5F2 [M+H]+ 505.2257, observed 505.2257; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.88 (d, J=6.4 Hz, 3H), 0.91 (d, J=6.4 Hz, 3H), 1.23 (s, 3H), 1.28 (s, 3H), 1.43 (br. s., 1H), 1.48-1.63 (m, 1H), 1.66-1.81 (m, 1H), 3.71 (dd, J=8.5, 5.7 Hz, 1H), 3.94-4.13 (m, 3H), 4.19 (d, J=18.4 Hz, 1H), 4.27-4.38 (m, 1H), 4.57 (d, J=18.4 Hz, 1H), 4.86 (dd, J=10.9, 4.8 Hz, 1H), 4.90 (s, 1H), 6.41 (d, J=2.1 Hz, 1H), 7.12-7.23 (m, 1H), 7.48-7.62 (m, 3H), 10.79 (s, 1H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].N1C=CC=CC=1.Cl[C:12]([O:14][CH:15]=[CH2:16])=[O:13]>CCOCC>[C:12](=[O:13])([O:14][CH:15]=[CH2:16])[O:4][CH2:3][CH2:2][Br:1]
Reactant: C=COC(=O)Cl
Reactant: OCCBr
Solvent: CCOCC
Solvent: c1ccncc1
Product: C=COC(=O)OCCBr
Temperature: 25 °C
Reaction time: 27 h
Yield: 78.8 %

Procedure:
To a 1 L 4-neck round bottom flask fitted with a mechanical stirrer, thermometer, condenser, dropping funnel and nitrogen blanket was added 31.2 g (250 mmol) of 2-bromoethanol, 21.4 g (270 mmol) of pyridine and 400 mL of ether. The reaction was cooled with an ice-water bath to less than 10° C. then 28.8 g (270 mmol) of vinyl chloroformate was added so that the temperature remained below 10° C. The reaction was stirred to room temperature for 27 hours. Then the organics were washed twice with 2N HCl, twice with 2N NaOH, then dried over magnesium sulfate. The solvent was removed on a rotary evaporator and the resulting oil was passed through a short silica gel column, to remove most of the color, to give 38.4 g (197 mmol, 78.8% yield). FTIR (neat, capillary) 3672.76, 3469.03, 3096.75, 2972.97, 2155.40, 2057.14, 1754.37, 1648.44, 1563.96, 1455.87, 1443.36, 1427.17, 1388.17, 1299.17, 1285.60, 1244.29, 1221.29, 1152.23, 1095.86, 1049.38, 988.10, 940.93, 897.08, 875.78, 828.81, 778.74, 738.01, 694.54, 663.28. NMR (CDCl3) 6.85-7.23 (1H,q), 4.40-5.10 (4H,m), 3.42-3.59 (2H,t).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>C1COCC1.O>[F:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:1][CH2:2][CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:20])[CH3:21])[CH:14]=[CH:15][CH:16]=3)[CH2:7][CH2:6]2)=[O:32])=[CH:26][CH:25]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)Nc3ccc(F)cc3)CC2)c1
Yield: 10.9 %

Procedure:
A solution of N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide (26.4 mg, 0.0870 mol), 1-fluoro-4-isocyanatobenzene (11.9 mg, 0.0870 mmol), in THF (1.00 mL) was stirred for 12 h at 25° C. The resulting crude mixture was diluted with water (10 mL), the aqueous layer was extracted with CH2Cl2 (3×20 mL). The combined organic layers were concentrated in vacuo and the residue was purified by preparative TLC using 2.5% of NH3 (2.0 M in methanol) in CH2Cl2 to give the desired product N-{3-[1-(3-{[(4-fluoroanilino)carbonyl]amino}propyl)-4-piperidinyl]phenyl}-2-methylpropanamide (4.18 mg, 10.9%): 1H NMR (400 MHz, CDCl3) 7.45 (q, 2H, J=4.7 Hz), 7.23–7.21 (m, 4H), 7.05 (t, 4H, J=7.8 Hz), 6.75 (m, 1H), 4.05 (m, 1H), 3.19 (s, 1H), 2.71 (m, 1H), 2.53 (m, 1H), 2.26–2.21 (m, 3H), 1.80–1.60 (m, 9H), 1.25 (d, 6H, J=6.4 Hz); ESMS m/e: 439.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O-:10])=O)[CH:5]=[CH:4][CH:3]=1.[K+].O=[C:13]1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1.[NH2:28][C:29]1[C:38]([CH3:39])=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][C:30]=1[CH3:40].C(N(C(C)C)CC)(C)C>CN(C)C=O.O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:28][C:29]2[C:30]([CH3:40])=[CH:31][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:37][C:38]=2[CH3:39])=[O:10])[C:5]([CH3:13])=[CH:4][CH:3]=1
Reactant: O=C([O-])c1cccc(Cl)n1
Reactant: COC(=O)c1cc(C)c(N)c(C)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(C)c(NC(=O)c2nc(Cl)ccc2C)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
To a suspension of potassium 6-chloropyridine-2-carboxylate (52 g, 265.8 mmoles) in dimethylformamide (676 mL) is added bis(2-oxo-3-oxazolidinyl)phosphonic chloride (115 g, 451.8 mmoles). The mixture is stirred at ambient temperature for 30 minutes. Methyl 4-amino-3,5-dimethyl-benzoate (42.9 g, 239.2 mmoles, see preparation 12) and diisopropylethylamine (115.9 mL, 664.5 mmoles) are added. The reaction is stirred at ambient temperature for 16 hours. The mixture is then poured into water (2000 mL) and is stirred for 30 minutes. The resulting solid is filtered and dried under reduced pressure at 45° C. The dry material is triturated with hexane (1400 mL) over 2 hours. The solid is filtered and dried under vacuum to give the title compound (69 g, 78%) as a white solid. Mass spectrum (m/z): 333.05 (M+1). 1H NMR (300 MHz, DMSO): 10.16 (s, 1H), 7.89 (d, J=8.2 Hz, 1H), 7.73 (s, 2H), 7.63 (d, J=8.2 Hz, 1H), 3.85 (s, 3H), 2.49 (s, 3H), 2.28 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].C(N(CC)CC)C.Cl[CH2:20][C:21](Cl)=[O:22].[H-].[Na+]>C1COCC1>[N+:8]([C:6]1[CH:5]=[CH:4][C:3]2[O:11][CH2:20][C:21](=[O:22])[NH:1][C:2]=2[CH:7]=1)([O-:10])=[O:9]
Reactant: O=C(Cl)CCl
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1COc2ccc([N+](=O)[O-])cc2N1
Yield: 39.6 %

Procedure:
Using 2-amino-4-nitrophenol (10 g, 65 mmol), triethylamine (11.7 mL, 84 mmol) and chloroacetyl chloride (5.4 mL, 68 mmol) in THF (150 mL) followed by sodium hydride (5.2 g of a 60% suspension in oil, 130 mmol) to yield the title compound as a grey solid (5 g, 33%). δH (DMSO-d6) 4.78 (2H, s), 7.15 (1H, d, J 8.9 Hz), 7.74 (1H, d, J 2.4 Hz), 7.84 (1H, dd, J 8.9, 2.6 Hz), 11.09 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([S:10][C:11]#[N:12])=[CH:6][C:3]=1[C:4]#[N:5].[H+].[B-:14]([F:18])([F:17])([F:16])[F:15].[N:19]([O-])=O.[Na+]>C(O)C.O>[F:15][B-:14]([F:18])([F:17])[F:16].[C:4]([C:3]1[CH:6]=[C:7]([S:10][C:11]#[N:12])[CH:8]=[CH:9][C:2]=1[N+:1]#[N:19])#[N:5]
Reactant: N#CSc1ccc(N)c(C#N)c1
Reactant: O=N[O-]
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CSc1ccc([N+]#N)c(C#N)c1
Yield: 95.4 %

Procedure:
To a solution of 2-amino-5-(thiocyanato)benzonitrile (2.00 g (11.4 mmol)) and 42% borofluoric acid (7.16 g (34.2 mmol)) in ethanol (10.0 ml), a solution of sodium nitrite (0.87 g (12.6 mmol)) in water (1.2 ml), was added dropwise under cooling with ice. The mixture was stirred under cooling with ice for 2 hours and crystals separated were filtered. The solid was washed with water, methanol and then ether, successively, and dried under reduced pressure to give 2.98 g (95%) of 2-cyano-4-(thiocyanato)benzenediazonium fluoroborate as white crystals.
Reaction SMILES: [C:1]1(C)[C:2]([S:7]([NH:10][C:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19](C)=[CH:18][CH:17]=3)[S:13][C:12]=2[C:23]([OH:25])=O)(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH3:27]N(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH3:52][O:53][C:54](=[O:57])[CH2:55][NH2:56].N1C(C)=CC(C)=CC=1C>CN(C)C=O>[CH3:52][O:53][C:54](=[O:57])[CH2:55][NH:56][C:23]([C:12]1[S:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:15][C:11]=1[NH:10][S:7]([C:2]1[CH:1]=[CH:6][C:5]([CH3:27])=[CH:4][CH:3]=1)(=[O:9])=[O:8])=[O:25]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COC(=O)CN
Reactant: Cc1ccc(-c2cc(NS(=O)(=O)c3ccccc3C)c(C(=O)O)s2)cc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: Cc1cc(C)nc(C)c1
Product: COC(=O)CNC(=O)c1sc(-c2ccccc2)cc1NS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
To a mixture of 5-phenyl-3-(toluene-4-sulfonylamino)-thiophene-2-carboxylic acid (prepared according to example 2) (50 mg, 0.134 mmol) in anhydrous dimethylformamide (1.4 ml) were added HATU 152 mg, 0.402 mmol), glycine methyl ester hydrochloride (20 mg, 0.161 mmol) followed by collidine (124 μl, 0.938 mmol). The mixture was stirred at room temperature for 1 hour, concentrated and pre-absorbed on SiO2. Purification chromatography (hexane to hexane:ethyl acetate; 6:4 to dichloromethane: methanol; 95:5) gave 47 mg of a mixture of {[5-Phenyl-3-(toluene-4-sulfonylamino)-thiophene-2-carbonyl]-amino}-acetic acid methyl ester and collidine. 1H NMR (CDCl3, 400 MHz) 7.76-7.73 (m, 2H), 7.61 (s, 1H), 7.57-7.54 (m, 2H), 7.42-7.36 (m, 3H), 7.24-7.22 (m, 2H), 6.19-6.17 (m, 1H), 4.14-4.12 (m, 2H), 3.79 (s, 3H), 2.35 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=1)[CH:6]=[CH:5]2.[NH2:20][C:21]1[CH:29]=[C:28]2[C:24]([CH:25]=[CH:26][NH:27]2)=[CH:23][CH:22]=1.[O:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][N:38]2[C:46]3[C:41](=[CH:42][C:43]([C:47]([OH:49])=O)=[CH:44][CH:45]=3)[CH:40]=[CH:39]2)[CH2:32][CH2:31]1>>[NH:27]1[C:28]2[C:24](=[CH:23][CH:22]=[C:21]([NH:20][C:15]([C:14]3[CH:18]=[CH:19][C:11]([N:7]4[C:8]5[C:4](=[CH:3][C:2]([NH:1][C:47]([C:43]6[CH:42]=[C:41]7[C:46](=[CH:45][CH:44]=6)[N:38]([CH2:37][CH2:36][N:33]6[CH2:32][CH2:31][O:30][CH2:35][CH2:34]6)[CH:39]=[CH:40]7)=[O:49])=[CH:10][CH:9]=5)[CH:5]=[CH:6]4)=[CH:12][CH:13]=3)=[O:16])[CH:29]=2)[CH:25]=[CH:26]1
Reactant: Nc1ccc2cc[nH]c2c1
Reactant: O=C(O)c1ccc2c(ccn2CCN2CCOCC2)c1
Reactant: Nc1ccc2c(ccn2-c2ccc(C(=O)O)cc2)c1
Product: O=C(Nc1ccc2cc[nH]c2c1)c1ccc(-n2ccc3cc(NC(=O)c4ccc5c(ccn5CCN5CCOCC5)c4)ccc32)cc1

Procedure:
Compound 972 was prepared according to the procedure described in Scheme IV from 4-(5-amino-1H-indol-1-yl)benzoic acid, 6-aminoindole, and 1-(2-morpholinoethyl)-1H-indole-5-carboxylic acid. [M+H]+ calcd for C38H34N6O3: 623.27; found 623.15.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[O:24][CH2:23][C@@H:19]3[CH2:20][NH:21][CH2:22][C@H:18]3[C@@H:17]2[C:25]2[CH:30]=[C:29]([I:31])[CH:28]=[CH:27][C:26]=2[CH3:32])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>>[C:35]([N:21]1[CH2:22][C@H:18]2[C@H:17]([C:25]3[CH:30]=[C:29]([I:31])[CH:28]=[CH:27][C:26]=3[CH3:32])[C@@H:16]([O:15][C@@H:13]([C:5]3[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:4]=3)[CH3:14])[O:24][CH2:23][C@@H:19]2[CH2:20]1)(=[O:37])[CH3:36]
Reactant: Cc1ccc(I)cc1[C@@H]1[C@@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC[C@@H]2CNC[C@H]21
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1C[C@H]2CO[C@H](O[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3cc(I)ccc3C)[C@@H]2C1

Procedure:
The title compound was prepared from (3aS,6R,7R,7aR)-6-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-7-(5-iodo-2-methylphenyl)octahydropyrano[3,4-c]pyrrole and acetic anhydride according to the procedures used for example 19. MS: (MH)+642.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][CH:6]([C:9]([O:11]C)=[O:10])[CH2:5][CH2:4]1)=[CH2:2].[OH-].[Na+].Cl.CCCCCC>CO>[CH:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1)=[CH2:2]
Reactant: C=CC1CCC(C(=O)OC)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CO
Product: C=C[C@H]1CC[C@H](C(=O)O)CC1
Temperature: 15 °C
Reaction time: 2 h

Procedure:
55.3 g of methyl 4-vinylcyclohexane carboxylate was dissolved in 60 mL of methanol, and was cooled to 15° C. Then, 100 g of 20% sodium hydroxide aqueous solution was added thereto. The solution was further stirred at room temperature for 2 hours, and then concentrated hydrochloric acid was added to make the system acidic. Extraction was performed with hexane, and then the organic layer was washed with saturated saline. The resultant product was dried over anhydrous sodium sulfate, and concentrated, to obtain 52.4 g of reaction mixture. 23.0 g of trans-4-vinylcyclohexane carboxylic acid was obtained by recrystallization from hexane.